Estudos in vitro e in vivo da atividade leishmanicida de novos derivados sintéticos

Abstract

The arsenal of drugs available for treating Leishmania infections is limited and presents high toxicity. Therefore, new, effective, and less toxic leishmaniasis treatments are still needed. In this work, two series of derivatives, containing a semicarbazone or hydrazide-N- acylhydrazone scaffolds was designed and synthetized as protease inhibitors. From these series, derivatives LASSBio 1483, LASSBio 1705, LASSBio 1707 and LASSBio 1736 highlighted, showing in vitro and in vivo leishmanicidal activities. Thus, these derivatives presented a potent leishmanicidal activity against amastigotes of L. major (IC50 of 1.5 µΜ to LASSBio 1483, 8.5 µΜ to LASSBio 1705 and 1.,9 µΜ to LASSBio 1707) , L. amazonensis (IC50 of 3.5 µΜ to LASSBio 1483 and 84.0 µΜ to LASSBio 1736), L. braziliensis (IC50 of 31.7 µΜ to LASSBio 1483, 8.0 µΜ to LASSBio 1705 and 5.3 µΜ to LASSBio 1736) and L. chagasi (IC50 of 53.3 µΜ to LASSBio 1707 and 57,6 µΜ to LASSBio 1736). Also, the leishmanicidal activity of derivatives LASSBio-1483, LASSBio 1705, LASSBio 1707 and LASSBio 1736 were mediated via induction of apoptosis as evidenced by externalization of phospholipids, despolarization of mitochondrial membrane and elevation of activation of caspases. The ultrastructural morphological effects against the parasite of LASSBio 1483 and LASSBio 1736 against L. chagasi promastigotes were also verified. The treatment of L. amazonensis -infected BALB/c mice with derivatives LASSBio 1483 (effect of 30.5% and 33.3% in infected ear, by p.o and i.p., respectively), LASSBio 1705 1483 (effect of 58.5% in infected ear and 61.1% in lymph node, i.p.), LASSBio 1707 (effect of 56.5% in lymph node, i.p.) and LASSBio 1736 (effect of 53.6% in infected ear, i.p.)or the treatment of L. chagasi - infected hamsters with LASSBio 1707 (effect of 53.6, i.p.)and LASSBio 1736 (effect of 46.0%, i.p.) led to a significant reduction of parasite burden when compared to controls that received PBS. The treatment with these derivatives did not result in hepatic or renal toxicity in these animals models of leishmaniasis. These data make LASSBio 1483, LASSBio 1705, LASSBio 1707 and LASSBio 1736 new lead-candidates against cutaneous and visceral leishmaniasis.